Almishaal Ali A, Mathur Pranav D, Hillas Elaine, Chen Liting, Zhang Anne, Yang Jun, Wang Yong, Yokoyama Wayne M, Firpo Matthew A, Park Albert H
Department of Communication Sciences and Disorders, University of Utah College of Health, Salt Lake City, Utah, United States of America.
Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
PLoS Pathog. 2017 Aug 31;13(8):e1006599. doi: 10.1371/journal.ppat.1006599. eCollection 2017 Aug.
Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.
先天性巨细胞病毒（CMV）感染是感音神经性听力损失（SNHL）最常见的非遗传性病因，但其听力损失机制仍不清楚。自然杀伤（NK）细胞通过NK细胞识别感染细胞表面表达的病毒编码m157配体的Ly49H细胞表面受体，在调节小鼠CMV感染中起关键作用。已发现这种Ly49H NK受体/m157配体相互作用介导脾脏和肺中宿主对CMV的抗性，但在肝脏中效果要差得多，因此尚不清楚这种相互作用在SNHL背景下是否重要。使用CMV诱导的迷路炎小鼠模型，我们已经证明Ly49H/m157相互作用介导颞骨中的宿主抗性。出生后第3天接种mCMV的缺乏功能性Ly49H的BALB/c小鼠在出生28天时出现严重听力损失和明显的外毛细胞损失。相比之下，具有Ly49H/m157相互作用能力的C57BL/6小鼠在相同mCMV剂量下听力损失最小，外毛细胞损失减轻。给予Ly49H阻断抗体或接种缺失m157基因的mCMV病毒株，使先前具有抗性的C57BL/6小鼠品系对听力损失的易感性与BALB/c小鼠品系相似，表明Ly49H/m157相互作用在mCMV依赖性听力损失中起直接作用。此外，在接种易感小鼠品系的颞骨中，NK细胞向感染部位的募集很明显。这些结果表明NK细胞参与了小鼠免受CMV诱导的迷路炎和SNHL的保护。
